Neuromuscular junction (hereinafter, may be also referred to as “NMJ”) constructed with a motor nerve terminal joined with a muscle is an essential synapse in controlling skeletal muscle by the motor nerve via the neurotransmitter acetylcholine. For appropriately controlling the skeletal muscle, it is necessary to form a high-density site (hereinafter, may be also referred to as “cluster”) through clustering of acetylcholine receptors (hereinafter, may be also referred to as “AChR”) in a postsynaptic region of a neuromuscular junction. It has been revealed that neuromuscular transmission disorders such as congenital myasthenic syndrome and myasthenia gravis may be developed when a high-density site of acetylcholine receptors is not normally formed (see, Nonpatent Documents 1 and 2).
It was reported that a glycoprotein, i.e., agrin, is secreted by motor nerve endings to activate MuSK that is a muscle-specific tyrosine kinase (see, Nonpatent Document 3). In addition, activation of MuSK that occurs in an agrin-dependent manner was reported to be essential in forming and maintaining the postsynaptic structure including a high-density site of acetylcholine receptors (see, Nonpatent Documents 4 and 5).
However, it was found that even before the muscle is controlled by the nerve, the high-AChR density site is formed in the vicinity of the endplate of the myotube in a manner independent to nerve and agrin, and in a manner dependent to MuSK. This finding suggests that the high-AChR density site is formed by a mechanism derived from the muscle in the initial stage of development (see, Nonpatent Documents 6 to 8).
Furthermore, agrin-independent formation of NMJ was found in mice in which a neurotransmission-dependent inhibitory action on clustering of AChR was eliminated by loss of acetylcholine productivity. This finding suggests that an activating factor of MuSK may be present in addition to agrin (see, Nonpatent Documents 9 and 10).
Moreover, as a result of genetic research, it was also indicated that not only appropriate growth of axon, but also normal expression of AChR gene, and clustering of AChR that subsequently occurs are controlled by a MuSK-dependent mechanism derived from the muscle (see, Nonpatent Documents 7 and 8).
Accordingly, clustering of AChR is essential for preventing neuromuscular transmission disorders, and it has been proven that the MuSK activation is prerequisite for clustering of AChR.    Nonpatent Document 1: A. G. Engel, K. Ohno and S. M. Sine, “Nature Reviews Neuroscience”, 4, 339 (2003)    Nonpatent Document 2: A. Vincent et al., “Annals of the New York Academy of Sciences”, 998, 324 (2003)    Nonpatent Document 3: D. J. Glass et al., “Cell”, 85, 513 (1996)    Nonpatent Document 4: S. J. Burden, “Genes and Development”, 12, 133 (1998)    Nonpatent Document 5: J. R. Sanes and J. W. Lichtman, “Nature Reviews Neuroscience”, 2, 791 (2001)    Nonpatent Document 6: T. M. DeChiara et al., “Cell”, 85, 501 (1996)    Nonpatent Document 7: W. Lin et al., “Nature”, 410, 1057 (2001)    Nonpatent Document 8: X. Yang et al., “Neuron”, 30, 399 (2001)    Nonpatent Document 9: T. Misgeld et al., “Proceedings of the National Academy of Sciences, U.S.A”, 102, 11088 (2005)    Nonpatent Document 10: W. Lin et al., “Neuron”, 46, 569 (2005)